PROJECT SUMMARY HIV infects the central nervous system (CNS) within days of initial exposure and has the propensity to cause progressive neuropathogenesis despite the intervention of antiretroviral therapy (ART). Infiltration by cytotoxic T cells (CTLs) into the CNS is a recognized feature in many neurodegenerative diseases that are associated with neuroinflammation, including multiple sclerosis, Alzheimer's disease, and various encephalitides but their role in HIV neuropathogenesis remains unknown. In HIV infection, CTLs constitute the majority of lymphocytes in the CSF, occur at a higher frequency than in many other neurological diseases, and are not normalized by ART. Our preliminary analyses show that this is already occurring within the first weeks after HIV exposure. Despite the large presence of CTLs in the CNS from the early stage of HIV infection, their role in neuropathogenesis remains mostly unknown. We hypothesize that hyperactivated CTLs in the CNS of untreated acute infected donors are a major cause of CNS damage. We further hypothesize that ART initiation during acute infection preserves beneficial HIV-specific CTLs in the brain, controlling viral reservoirs. Finally, we hypothesize that among individuals who initiate treatment during chronic infection T cell unique clones persist in the CNS after treatment initiation and are associated with residual CNS damage in this setting. The major objective of this proposal is to determine the neuropathogenic mechanisms of CTLs during HIV infection in acute and chronic infection prior to and after ART initiation. To achieve this objective, we will analyze CTLs in the CSF from a highly unique cohort enrolling in Bangkok, Thailand (U.S. Military HIV Research Program study RV254), that is recruiting subjects in the earliest stages of acute infection and compare them to chronically infected subjects. At enrollment, all subjects initiate ART, PBMCs and CSF samples are collected and markers of neuroinflammation in the CSF, magnetic resonance spectroscopy and neuropsychological testing performance are measured at baseline, weeks 24 and 96. We will be able to determine how early are CTLs entering the CNS and causing damage, define the cellular mechanisms involved in the CTL-mediated neuropathogenesis prior to treatment and whether early antiretroviral treatment decreases HIV reservoir in CNS and prevents residual damage persisting under ART. Understanding the neuropathogenic mechanisms that are established in the first days following exposure and whether they persist with ART is of critical importance to reduce the burden of CNS injury among the HIV-infected population. The results of this study will pave the way for the development of therapeutic strategies to limit CTL-mediated CNS damage and preserve cognitive function in HIV-infected patients.